Corticostriatal-hypothalamic circuits and opioid seeking

点击翻译按钮获取中文摘要

PROJECT SUMMARY Opioid use disorder (OUD) is characterized by excessive motivational drive to seek drugs and/or a loss of inhibitory top-down control of drug seeking, resulting in relapse and recurrent drug seeking. Preliminary data from our lab show two opposing circuits originating from the infralimbic (IL) cortex, one that ‘drives’ heroin seeking behavior and one that ‘limits’ heroin seeking behavior. These ‘driver’ and ‘limiter’ pathways project from the IL to subcortical reward and motivational hubs, such as the nucleus accumbens shell (NAsh) and the lateral hypothalamus (LH). Our lab has shown that the ILLH circuit drives heroin seeking and relapse, while the ILNAsh pathway limits heroin seeking. The functional downstream outputs of the ILNAsh limiter pathway are, however, currently unknown. The LH is well characterized as a driver of motivated behavior, and the GABAergic inhibitory projection from the NAshLH projection has been implicated in the suppression of drug seeking behavior after extinction, suggesting inhibition of the LH is a mechanism for decreasing drug seeking. In Aim 1, I will investigate the NAshLH pathway as a potential limiter of heroin seeking, using chemogenetic manipulations to alter activity in this circuit and measure behavioral outcomes on drug seeking in a preclinical model of OUD. I propose that this pathway is an extension of the previously identified ILNAsh limiter pathway, involving an ensemble of neurons in the NAsh that both receive input from the IL and project to the LH. I hypothesize this unique neuronal population will ultimately be responsible for limiting heroin-seeking behavior. The disynaptic ILNAshLH limiter pathway interposes a GABAergic relay between the IL and LH, providing a potential mechanism by which the limiter pathway function is actualized. Thus, it is possible that the disynaptic ILNAshLH limiter circuit and the ILLH driver circuit converge on the LH, where the inhibitory projection from the NAsh may compete with the excitatory projection from the IL to control heroin seeking. Preliminary data from the Peters lab has shown that LH orexin neuron number correlates with metrics of heroin motivation, and systemic blockade of orexin receptors with a dual orexin receptor antagonist (DORA) decreases heroin relapse, strongly implicating the LH orexin neuron population in controlling heroin-seeking behaviors. Further, these LH orexin neurons project to the IL cortex, and blockade of orexin receptors within the IL cortex dampens motivated behaviors. In Aim 2, I will use chemogenetics to determine whether the LHIL pathway drives drug seeking. I will then determine whether intra-IL orexin receptor activation is required for heroin seeking, using brain-site specific pharmacology. If indeed the limiter and driver pathways are competing within the LH, this orexinergic feedback to the IL cortex might be expected to strengthen the driver, leading to an imbalance in heroin seeking. The proposed experiments will identify novel circuits and receptor mechanisms that influence heroin-seeking behavior. It is essential that we further our understanding of the neural circuitry underlying OUD, as these findings will illuminate potential targets for new therapeutic strategies.